Oxypyrimidine is an important precursor in the manufacture of a class of thioesters of oxypyrimidine which have insecticidal and acaricidal activity as disclosed in U.S. Pat. No. 2,754,243. One of these compounds, O,O-diethyl-O-(2-isopropyl-4-methyl-6-pyrimidyl) thiophosphate is well-established commercial product under the trademark DIAZINON.RTM.. As the product is manufactured and sold in large quantities, each improvement in the manufacture of oxypyrimidine is of economic importance. While the discussions which follow are primarily directed to the 2-isopropyl embodiment they also apply to its 2-cyclopropyl homolog which is also a precursor for insecticidal compounds.
The n-propyl homolog reacts similarly.
Oxypyrimidine presently is synthesized by way of three reaction steps (Equations I, II, III): ##STR1##
Equations I and II above are optimized by the solvents and conditions taught in U.S. Pat. No. 4,111,976.
In the search for more economical processes for the manufacture of oxypyrimidine various expedients have been proposed such as the optimized ring closure disclosed in U.S. Pat. No. 4,014,879. The reaction is initiated in a single vessel in aqueous alkali as the solvent medium and completed and polished in a subsequent vessel. To achieve commercial yields excesses of 30 to 35% methylacetoacetate are required.
Utilizing water as the sole reaction solvent required a large excess of acetoacetic acid ester, preferably about 30 to 35% excess of methyl acetoacetate (MAA). The excess MAA was required because of competing hydrolysis side reactions. Attempts were made to reduce the required 30 to 35% excess of MAA by using water-in-soluble solvents with or without phase-transfer catalysts. It was postulated that the MAA would distribute primarily in the organic solvent and would be protected from hydrolysis. Diketene was also used in the two-phase system to see if it could be substituted for MAA.
In practice it was found that the introduction of a two-phase solvent system (solvents used were toluene and isopropyl ether) made no difference in yield. The water-immiscible solvent had little positive or negative effect on the reaction. It was believed that the reaction took place entirely in the aqueous phase and that all reactants were present initially in the aqueous phase.
The required excess of methylacetoacetate has been reduced to about 5 mole % by the invention of U.S. patent application Ser. No. 368,771, filed Apr. 15, 1982 and commonly assigned. The aqueous alkali reaction medium is modified by replacing all or most of the water with a lower alkanol. Yields of 80 to 85% are obtained with this reduced methylacetoacetate excess in a stirred continuous flow reactor.
As stated above, U.S. patent application Ser. No. 368,771 utilizes a lower alkanol, specifically, methanol or ethanol to provide a commercially variable reaction scheme. This is an extension of the process of U.S. Pat. No. 4,111,976 wherein the amidine is formed in the presence of a lower alkanol (methanol or ethanol) as the reaction medium.
However, the three-stage procedure of Equations I, II and III, mentioned above, was still preferred, especially after the first stage reaction was optimized in accordance with the procedure of U.S. Pat. No. 4,111,976 and Ser. No. 368,771 wherein methyliminoisobutyrate hydrochloride was prepared by reacting isobutyronitrile (IBN), hydrogen chloride (HCl) and methanol (MeOH) in methanolic solution continuously containing an excess of HCl.
The second and third stages were carried out using methanolic water as the reaction solvent for the amidine formation (Equation I) and methanol as in Ser. No. 368,771 for the ring closure (Equation III).
It was believed that the methanolic solution reduced the rate of the two competing hydrolysis reactions, IV and V which occurred during the ring closure reaction of Equation III.
The three reactions simultaneously occuring in parallel are: ##STR2##
The hydrolysis of MAA and amidine.HCl is highly undesirable as these are expensive raw materials and the requirements for oxypyrimidine run to about 10 million pounds per year.
In order to effect proper economies, the three concurrent reactions, via their kinetics were studied.
An examination of the kinetics of the three reactions indicates that the ring closure oxypyrimidine formation (Equation III) is second order, i.e., dependent upon the concentrations of both MAA and amidine.HCl, while both MAA hydrolysis and amidine.HCl hydrolysis, (Equations IV and V) are pseudo-first order, i.e., dependent only on the concentration of MAA or amidine.HCl, because the concentration of H.sub.2 O present in the NaOH will be much greater than either reactant. This dictates then that for minimum hydrolysis of MA and amidine. HCl, and, therefore, for maximum yield of oxypyrimidine, the contact between MAA, amidine.HCl, and NaOH/H.sub.2 O at high pH should be kept to a minimum.
It is also noted that by replacing most of the water with methanol, the reaction rate of the ring closure of Equation III was halved but the reaction rate of the hydrolysis of Equation IV and V were seen further reduced (about 1/3 to 1/5).
In a constant flow stired tank rector, the minimal contact between nascent reactants is difficult to maintain because the vessel contents are being constantly and turbulantly mixed with the incoming raw materials. However, in a plug flow reactor having concurrent progressive flow the contents are constantly moving away from the incoming raw materials, thereby minimizing hydrolysis losses and maximizing oxypyrimidine yield.
However, plug flow reactors commonly used in continuous flow reaction unit operations, are difficult to use when the reaction products or by-products contain solids. A close approximation to such plug flow reactors is the multi-stage reactor (MSR) comprising a series of chambers (stages) connected by restricted flow orifices to ensure limited dwell time for the reactants at each stage but preventing back mixing of the incoming raw materials, ensuring constant controlled movement of the reaction contents away from the incoming raw materials.